1. Field of the Invention
The present invention is directed to an osmotic pump capable of providing controlled delivery of a desired active agent. Specifically, the present invention includes an osmotic pump that is configured to automatically provide ascending release of active agent without the need for further manipulation of the osmotic pump after administration to an environment of operation.
2. State of the Art
The benefits provided by controlled delivery of active agents for the treatment of disease are well recognized in the art and various approaches have been taken to realize the goal of delivering active agents at desired rates over predetermined periods of time. One approach involves the use of implantable drug delivery devices. Controlled delivery of a beneficial agent from an implantable device over prolonged periods of time has several potential advantages. For instance, use of implantable delivery devices generally assures patient compliance, as implantable devices are not easily tampered with by the patient and can be designed to provide therapeutic doses of beneficial agent over periods of weeks, months, or even years without patient input. Moreover, because an implantable device may be placed only once during its functional life, implantable devices may offer reduced site irritation, fewer occupational hazards for patients and practitioners, reduced waste disposal hazards, decreased costs, and increased efficacy when compared to other parenteral administration techniques, such as injections, which require multiple administrations over relatively short time intervals.
Various different implantable controlled delivery devices are known in the art, and various different mechanisms have been employed for delivering active agent from implantable devices at a controlled rate over time. In one approach, implantable drug delivery devices are designed as diffusional systems. For example, subdermal implants for contraception that operate by diffusion are described by Philip D. Darney in Current Opinion in Obstetrics and Gynecology 1991, 3:470–476. In particular, the Norplant® system requires the placement of six levonorgestrel-filled silastic implants under the skin and provides protection from conception for up to five years. The Norplant® implants operate by simple diffusion, that is, the active agent diffuses through the polymeric material at a rate that is controlled by the characteristics of the active agent formulation and the polymeric material. In addition, Darney describes biodegradable implants, namely Capranor™ and norethindrone pellets. These diffusional systems are designed to deliver contraceptives for about one year and then dissolve. The Capranor™ systems consist of poly(ε-capralactone) capsules that are filled with levonorgestrel and the pellets are 10% pure cholesterol with 90% norethindrone.
Implantable infusion pumps represent another approach to the design of implantable devices capable of providing controlled release of active agents over prolonged periods of time. Such pumps have been described for delivering drugs by intravenous, intra-arterial, intrathecal, intraperitoneal, intraspinal and epidural pathways. Implantable infusion pumps are usually surgically inserted into a subcutaneous pocket of tissue in the lower abdomen. Exemplary regulator-type implantable pumps capable of constant flow, adjustable flow, or programmable flow of active agent formulations include pumps available from, for example, Codman of Raynham, Mass., Medtronic of Minneapolis, Minn.; and Tricumed Medinzintechnik GmbH of Germany. Further examples of implantable infusion pumps are described in U.S. Pat. Nos. 6,283,949; 5,976,109; and 5,836,935. Even further, implantable infusion pump systems for pain management, chemotherapy and insulin delivery are described in the BBI Newsletter, Vol. 17, No. 12, pages 209–211, December 1994. Implantable infusion pumps typically provide for more accurately controlled delivery than simple diffusional systems.
A particularly promising approach to controlled delivery of active agent from implanted devices involves osmotically driven devices. Such devices are typically simple in design, but capable of providing consistent and reproducible delivery of a range of active agents at a controlled rate over periods of days, weeks, months, or even years. Exemplary osmotic pumps that may be designed for implantation in a human or animal subject are described in, for example, U.S. Pat. Nos. 5,234,693; 5,279,608; 5,336,057; 5,728,396; 5,985,305; 5,997,527; 5,997,902; 6,113,938; 6,132,420; 6,217,906; 6,261,584; 6,270,787; 6,287,295; and 6,375,978, which are assigned to ALZA corporation of Mountain View, Calif., and are incorporated in their entirety herein by reference.
Implantable osmotic delivery devices are commonly referred to as “osmotic pumps” and typically include a reservoir, an expandable osmotic material, a drug formulation, and at least one delivery orifice. Where the expandable osmotic material and the drug formulation are formed of separate materials, the expandable osmotic material and the drug formulation may be separated by a member, such as a piston, which is movable within the reservoir. At least a portion of the reservoir included in an osmotic pump is generally semipermeable, allowing water to be taken into the system while working to prevent or minimize the undesired escape of materials forming the expandable osmotic material or the drug formulation from the reservoir. The osmotic material included in an osmotic pump typically draws water from the environment of operation into the osmotic pump through the semipermeable portion of the reservoir. As water is drawn into the device, and in particular into the osmotic material, the osmotic material expands and drug formulation is discharged through the delivery orifice of the osmotic pump at a chosen release rate or release rate profile.
Though they have proven useful for providing drug delivery at controlled rates, implantable osmotic pumps have been typically designed to provide substantially zero-order release rates of a desired active agent. However, there are instances where it would be desirable to provide an implantable, controlled release delivery device that delivers active agent at an ascending release rate after the device is introduced into a desired environment of operation. As it is used herein, the term “environment of operation” refers to any environment into which an osmotic pump can be introduced and is capable of supporting operation of the osmotic pump over a desired period of time. In particular, an implantable device that provides an ascending release rate of drug would be useful for the delivery of drugs that require an increase in dose over time in order to maintain efficacy or where the subject would benefit from a dosing regimen that starts with a relatively low initial dose but progresses to or terminates with a relatively higher dose of drug.
In U.S. Pat. Nos. 6,436,091; 6,464,688; and 6,471,688 and in U.S. Patent Application Publication 2003/0032947 A1, the contents of each of which are incorporated herein by reference, Harper et al. disclose implantable osmotic pumps that can be designed to allow the increase of the active agent release rate post implantation. However, the designs of the dosage forms described in these patent references are not without disadvantages. In particular, each of the designs disclosed in these references requires physical manipulation of the osmotic pump in order to increase the rate at which active agent is delivered post implantation. For example, the devices taught in U.S. Pat. Nos. 6,436,091; 6,464,688; and 6,471,688 include multiple rate controlling membranes, with one or more rate controlling membranes being initially sealed from permeation by aqueous fluid from the environment of operation. To increase the release rate provided by such devices, the seal formed over one or more of the initially sealed rate controlling membranes is breached by, for example, a lancet inserted within the subject. Alternatively, U.S. patent application Publication 2003/0032947 A1 teaches implantable osmotic pumps that incorporate the piercing mechanisms necessary to compromise the seals initially formed over one or more rate controlling membranes included in the devices. Though such a design does not require insertion of a lancet, the physical manipulation required to actuate the integrated piercing mechanisms may still result in patient discomfort and introduces an amount of uncertainty as to whether the implant has been properly manipulated to cause an increase in rate at which active agent is delivered.
It would be an improvement in the art, therefore, to provide an implantable osmotic pump that provides an ascending release rate of active agent without the need for further manipulation post implantation. In particular, it would be desirable to provide an implantable osmotic pump that automatically provides a desired ascending release rate profile post implantation. Ideally, the design of such a device would not only facilitate delivery of a wide range of active agents and active agent formulations, but would also enable the fabrication of implantable osmotic pumps providing a wide range of different ascending release rates.